CA1174680A - Imidazole derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Compounds of the general formula:
(I) and acid addition salts thereof;
in which Ar and Ar1 which may be the same or different, each represent an aromatic radical which may be susbtituted one or more times by substit-uents selected from the following:
halogen; carboxy;
lower alkyl; carboxyalkyl;
lower alkoxy; cyano;
alkylenedioxy; carboxamido;
aralkoxy; di-lower alkylamino;
aryloxy; nitro; and trihalomethyl; lower alkyl sulphonyl provided that one of the groups Ar and Ar1 carries at least one alkoxy, alkylenedioxy, carboxy or carboxy-alkyl substituent; and Alk1 and Alk2, which may be the same or different, each represent an alkylene group containing from 1 to 8 carbon atoms which may be substituted one or more times by lower alkyl;
X and Y which may be the same or different represent oxygen, nitrogen or sulphur; and in which the imidazole ring may be substitued by one or more lower alkyl substituents have antithrombotic activity. A representative compound is 1-[2-[(4-methoxyphenyl)methoxyl-3-[(4-methoxyphenyl)methoxylpropyl]-1H-imidazole. The compounds are useful as antithrombotics.

Description

1~74~i~3C) This invention relates to imidazole derivatives, the production thereof, to compositions containing them and to their use in pharmacy.
We have found that compounds of the general formula: N
¢9 N

~H2 ~ Cl~ - X - Alk2 - Ar C~2- Y - Alkl - Arl in which Ar and Arl which may be the same or different, each represent an aromatic radical which may be substit-uted one or more times by substituents selected from the following list:-halogen; carboxy;
lower alkyl; carboxyalkyl;
lower alkoxy; cyano;
alkylenedioxy; carboxamido;
aralkyloxy; di-lower alkylamino;
aryloxy; nitro; and trihalomethyl; lower alkyl sulphonyl provided that one of the groups Ar and Ar1 carries at least one alkoxy, alkylenedioxy, carboxy or-carboxy-alkyl substituent; Alkl and '~

Alk2 which may be the same or different each representsan alkylene group containing from l to 8 carbon atoms which may be substituted one or more times by lower alkyl; X and Y which may be the same or different represent oxygen, nitrogen or sulphur; and in which the imidazole ring may be further substituted by one or more lower alkyl substituents. These compounds and acid addition salts of such compounds have marked ~harmacologica1 activity, in particular as antithrombotics.
io The invention therefore provides such compounds.
It includes all optical isomers and racemic mixtures the~eof.
The antithrombotic activity of the compounds of the invention has been determined by their ability to inhibit 15 prodlJction of thromboxane A2 (TxA2) by blood platelets the synthesis of which is an important factor in the aggregation of platelets and the initiation of thrombosis (R.J. Gryglewski, C~C Crit. Rev. Biochem., (1980), 7(4), 291).
Thus, there is evidence that thrombosis is determined by the balance of products derived from prostaglandin cyclic endoperoxides between the thrombogenic TxA~ released on platelet aggregation and the thrombolytic prostacyclin (PGI2) formed in the vessel walls. Blocking or reducing 25 tlle production of Tx~2 is useful in the treatment and prophylaxis of thrombosis.
Standard in vitro and in vivo pharmacological test-metllods can be cmployed in assessing the antithrombotic activity of tlle compounds according to the invention.

117~80 For example the compound of Example 1 was found in in vitro tests to inhibit (i) the generation of thromboxane A2 as determined by radioimmuno-assay of its stable metabolite, Tx82 (New England Nuclear, Thromboxane B2 [3H]
RIA kit, Catalogue No. NEK 007; and (ii) the aggregation of human platelet rich-plasma (G.V.R. Born et al, Nature, (1962), 194, 927).
Furthermore, the compound of Example 1 at concentrations equivalent to these which inhibit TxA2 formation was found not to significantly effect production of prostacyclin ln cultured endothelial cells as determined by radioimmuno-assay of the stable metabolite of prostacyclin, 6-keto PGF 1~ (New England Nuclear 6-keto PGF 1~ RIA kit, Catalogue No. NER 008).
In addition, in vivo tests carried out of pla~telet aggregation in the male retired breeder rat model (R.N.
Saunders et al, Lab. ~nimal Sci. (1977) 27, 757) have shown compounds of formula 1 are more active than the clinically prescribed antiaggregatory compounds such as aspirin, dipyridamole and sulphinpyrazone.
The active compounds are useful wherever it is desired to inhibit platelet aggregation and/or to reduce the adhesive character of platelets, and consequently. to treat or prevent the formation of thrombosis in mammals, including man. For example, the compounds may be useful in the treatment and prevention of myocardial infarcts, cerebro-vascular thrombosis, ischaemic peripheral vascular disease and thrombo-embolic microangiopathy; to ~17'~80 treat and prevent post-opcrative thrombosis; and to promote patency of vascular grafts following surgery; they may also be useful in the prevention and treatment of migraine.
The compounds according to the invention have at least one alkoxy, alkylenedioxy, carboxy or carboxyalkyl sub-stituent on one of the groups Ar and Arl. The alkoxy group preferably contains 1-6 carbon atoms, in particular 1-4 carbon atoms. Specific alkoxy groups are methoxy and ethoxy.
The alkylenedioxy group preferably contains 1-3 carbon atoms in the alkylene chain. A specific alkylenedioxy substituent is methylenedioxy. The carboxyalkyl group is preferably carboxy lower alkyl, in particular those wherein alkyl is methyl or ethyl.
The groups ~lkl and ~lk2 preferably contain 1 to 4 carbon atoms in the alkylene chain.
The term 'lower' c~s used herein to apply to alkyl or alkoxy groups, or moieties containing them, means that such groups, preferablv contain 1 to 6, in particular 1 to 4 carbon ator,ts.

By the tcrm aryloxy as used herein we mean in particular phenoxy. ~lso by the term aralkyloxy as used herein we mean in particular benzyloxy.
Prefcrrcd compounds according to the invention are those in which ~r and ~r are phenyl, napththyl, pyridyl, furanyl or thienyl, substituted as specified above.
rreferably the alkoxy, alkylenedioxy, carboxy or carboxyalkyl substituent is situated on the group Ar or on both groups Ar and Arl. Preferred --1~74~8~
. .

meanings for the group Ar are phenyl, furanyl, thienyl .or pyridyl optionally substituted by one or more of the following substituents, namely, lower alkoxy, methylene-dioxy, lower alkyl, carboxy and carboxyalkyl.
Specific preferred compounds according to the invention are those, the preparation of which, is des-cribed in the Examples.
The compounds of the general formula I, according to the invention may be prepared by reacting a compound of the formula (~
N

¢N~
~ Q II

15~ y-AlklAr in which Y, Alkl and Arl have the meanings given herein-beforc and in which the imidazole ring may be substituted with one or more lower alkyl substituents with a compound of the general (III):-20~ ~lk Ar in which Q represents a group of the fromula XH in which X has the meaning given hereinbefore and Ql represents a nucleophilic-displaceable group or vice versa and Alk2 and Ar have the meanings given hereinbefore.

This process may also be applied to the production 117~i8~) of a compound of formula I in which X, Y, Alkl, Alk2, Ar and Arl have the meanings given hereinbefore, with .
the proviso that X-Alk2-~r is identical to Y-Alkl-Arl, which comprises reacting a compound of the general formula IIa:-h-- N

N ~ IIa ~ Q
- Q

in which Q has the meaning given hereinbefore with an appropriate amount of a compound of the formula III:-QlAlk2Ar IIIin which Ql has the meaning given hereinbefore. The compounds may be isolated as such or as a pharmaceutically acceptable acid addition salt or one such salt may be converted to another.
Thus, the compounds of formula I where X is oxygen may be prepared by reacting a compound of the general formula (II):-~N ~
II

~ -Alkl-Ar in which -Q is -Xll and X is oxygen and Alkl, Y.and Arl are defined as hereinbefore and the imidazolyl-ring r.lay be further substituted with a compound of the general formula III:-Ql-~lk2-Ar III

in which Ql represents a suitable nucleophilic-displaceable group such as a halogen atom or a mesylate, tosylate etc., and Alk2 and Ar are defined as hereinbefore. The product may be isolated as the base or as an acid addition salt. The reaction is preferably carried in the presence of a suitable strong base, in particular an alkali metal hydride such as sodium hydride in an anhydrous aprotic organic solvent under an inert atmosphere. The reaction may be conducted at either room temper-ature (15-20C) or to somewhat elevated temperature (of the order of 75C).
The compounds of formula II may be prepared from the parent substituted oxirane of the general formula (IV):

Cl~ - CH - CH2 - Y - Alkl - Arl IV
by reacting these with imidazole or substituted imidazole, which is preferably in the form of an alkali metal salt, e.g. as the sodium salt. The compound of formula IV may be obtained by reaction of a halohydrin of the formula (V):
/ \
25C~l2 ~ Cl~ - C~l2 - Hal V

~17~
. i .~

in which Hal represents halogen with a compound of the formula (VI):
Ho-Alkl-Arl VI

where Alkl, and Arl are defined as hereinbefore preferably in the presence of a suitably strong base such as sodium hydride as described above.
When X=NH compounds of formula I may be pre-pared by reacting a compound of the general formula II in which Q=XH where X=NH and Alkl, Y and Arl are defined as hereinbefore with a compound of general formula ~I in which Ql, Alk2 and Ar are defined as hereinbefore. The product may be isolated as the base or as an acid addition salt. The reaction is pre-ferably carried out in the presence of a base suchas triethylamine in an anhydrous aprotic sol~ent and advantageously at a temperature of the order of 80C.
The compounds of formula II-in which X=NH may be prepared by reduction of compounds of formula VII
below with suitable reducing agents e.g. lithium aluminium hydride in an inert solvent. The compound of formula (VII):
r-~N

~ N ~ VII
~ N3 ,.

~ y-Alkl-Ar 1~17~

may be obtained by reaction of a mesylate (R=CH3) or a tosylate (R=4-CH3C6H4) of general formula VIII below with an alkali azide (e.g. sodium azide) in an aprotic solvent at elevated temperature (e.g. dimethyl-formamide at 100C).
Compounds of formula (VIII):

~ 0-S02R VIII
Y-Alkl Ar may be prepared from the compound of general structure II
in which X=0 (Q=0l~) by reaction with either methyl sulphonyl chloride or p-toluene sulphonyl chloride using standard conditions.
The compounds of general formula I in which X=S
may be prepared by reacting compounds of for~ula VIII
above in which Alkl, Ar, R and Y are as hereinbefore defined, with a mercaptan of the formula Ql-Alk2-Ar IX
where Alk2 and Ar are as hereinbefore defined and Ql=SH
preferably in the presence of a suitably strong base (e.g. sodium hydride) in an inert solvent (e.g. dimethoxyethane) ~17~BO

The compounds of general structure I can be prepared as the individual optical isomers for instance by synthesis from an~appropriate starting material of known optical integrity. Thus the compound of general formula X having S-stereochem-istry in which Ar, Arl, Alkl and Alk2 are defined as hereinbefore, with the proviso that Ar=Arl and Alkl=Alk2, N
.~
~ "0-Alk2-Ar X
H ~ 0-Alkl-Ar may be obtained by reacting the corresponding S-diol (XI): ~ N

N XI
~ , OH
H ~

with two equivalents of the compound of general formula III defined hereinbefore in which Ar, Alk2 and Ql are as herein-before defined. The reaction is preferably carried out in the presence of a suitable strong base, such as sodium hydride in an anhydrous aprotic solvent under an inert atmosphere. Where Ar or Arl contains a carboxy substituent it can be derived by the base hydro-lysis of the parent ester, that is the compound in which the substituent is carboxy alkyl.

"", 1~74~i~30 The diol of structure XI may be obtained by react-ing the known S-isopropylidene glycerol, 4-methylphenyl sulphonate (E. Baer and H.O.L. Fischer, J. Amer. Chem.
Soc., (1948), 70, 609) with imidazole or a substituted imidazole at elevated temperature (of the order of 80C) in a suitable dry polar solvent (e.g. acetonitrile), followed by an acidic work-up to remove the ~lycol protecting-group.
Alternatively, compounds of general structure XII
having the R-stereochemistry in which Ar, Arl, Alkl and Alk2 are defined as hereinbefore, with the proviso that Ar=Ar1 and Alkl=Alk2, fi--N

~ N ~ XII
~ O - Alk2 - Ar H ~ O - Alkl - Ar may be obtained by reacting the corresponding R-diol YIII

~ N ~
~ ~H XIII

Il OH

with 2 equivalents of a compound of general formula III
in which Ar, Alk2, and Ql are defined as hereinbefore.
The reaction is preferably carried out in the presence of a suitable strong base, such as sodium hydride in an anhydrous aprotic solvent under an inert atmosphere.
The R-diol of structure XIII may be obtained by the cleavage of the R-benzyl ether of structure XIV.
The reaction is preferably carried out under an atmos-phere ~ N

N
~ OH
H ~ O ~ XIV

of hydrogen in the presence of a suitable catalyst such as palladium absorbed onto charcoal in a suitable solvent (e.g. ethanol).
The benzyl ether of structure XIV may be obtained by reacting the compound of structure XV with imidazole CH8 ~ S2 - O
H " ~

XV
or a substituted imidazole at elevated temper.ature (of the order of 80C) in a suitable dry polar solvent (e.g.
acetonitrile).

117468~) The tosylate of structure XV may be obtained by reacting the diol of structure XVI with p-toluene -OR

H --- _OH
XVI

sulphonyl chloride using standard conditions.
The diol of structure XVI may be obtained from the S-isopropylidene ether of structure XVII by acid hydrolysis -X
H---- ~0 L o ~ XVII

using a suitable mineral acid (e.g. hydrochloric acid) in a suitable solvent such as acetone.
Finally, the compound of structure XVII may be obtained from S-~,~-isopropylidene glycol by reaction with a benzyl halide. The reaction is preferably carried out in the presence of a suitable strong base (e.g. sodium hydride) in an anhydrous aprotic solvent under an inert atmosphere.

1174~(~

The compounds according to the invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such route, and in a dose effective for the treatment intended.`
Accordingly, the invention provides a pharmaceutical composition comprising one or more compounds according to the invention in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
The composition may for example be applied orally or by injection.
For oral administration, the pharmaceutical composition may take the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit contained in a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. These may with advantage contain an amount of active ingredient from 5 to 250 mg preferably 25 to 150 mg. A suitable daily dose for a mammal may vary widely depending on the condition of th-e patient and other factors. However, a dose of from 0.1 to 300 mg/kg body weight, particularly 0.5 to 10 mg/kg body weight preferably 5 mg to 10 mg/kg body weight may be appropriate.
The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water for injection may be used as a suitable carrier. A suitable daily dose of about 0.1 to 100 mg 117~

per kg body weight injected per day in multiple doses depending on the disease being treated. A preferred daily dose would be from 1 - 30 mg/kg body weight.
As indicated, the dose administered and the treatment regimen will be dependent, for example, on the disease, the severity thereof, on the patient being treated and his response to treatment and therefore may be widely varied.
The pharmaceutical compositions may be prepared by techniques well known in the art and described, interalia, in Remington's Pharmaceutical Science, Mach Publishing Co., Easton, Penn., 1965. .
The following Examples illustrate the invention:

1=l2-~(4-Methoxyphenyl~methoxyl-3-l~4-methoxyphen methoxylpropyl]-lH-imidazole a~ 2.3-Epoxypropyl-4-methoxybenzyl ether A solution of 4-methoxybenzyl alcohol (800g, 5.8M) in dry tetrahydrofuran (1200ml) was added dropwise to a stirred slurry of sodium hydride (280g of a 60%
dispersion in oil, 7.8M) in dry tetrahydrofuran (600ml) at -5C and under a gentle stream o dry nitrogen. The mixture was allowed to warm up to room temperature and stirred until hydrogen evolution ceased. The resulting slurry of the sodium alkoxide was cooled to -5C and 11`7~

treated ~Jith epibromohydrin (8609, 6.3M) at a rate such that the temperature remained below 5C. The reaction mixture was allowed to warm gradually to room temperature and left stirring for 12 hours.
The final mixture was filtered and washed with methanol. The combined filtrate and washings were evaporated to dryness under reduced pressure to afford the crude product (250g). Further purification of this crude product by column chromatography (silica gel, 2596 hexane in chloroform to 10% methanol in chloroform) afforded 2,3-epoxypropyl-4-methoxybenzyl ether as a pale yellow oil.
lH-NMR (~-CDC13): 2.70 (m,2H), 3.20 (m,lH), 3.65 (m,2H), 3.37 (s,3H), 4.73 ~s,2H) and 7.15 ( q,4H).
b) 1-~2-Hydroxy-3-~(4-methoxyphenyl)methoxylpropyll-lH-imidazole

2,3-Epoxypropyl-4-methoxybenzyl ether (1009, 0.725~) in dry tetrahydrofuran (200ml) was treated with imidazole (44.4g, 0.765M) and heated under reflux for 16 hours.
The solution was filtered and the solvent was evaporated off under reduced pressure to give a brown solid which was recrystallised from 10% water-propan-l-ol to give 1-12-~lydroxy-3-[(4-methoxyphenyl) methoxylpropyll-lH-imidazole (839) as a colourless crystalline solid, m.p.
96-98C.

:1174~80 .

c) 1-~2-l(4-methoxy~h~ny~ hQ~y1-3-l(4-methoxvph~nyl) methoxylpropyll-lH-imidazole A solution of 1-12-hydroxy-3-[(4-methoxyphenyl)methoxy]propyl]-lH-imidazole (2069, 0.79M) in dry tetrahydrofuran (3700ml) was added dropwise to a stirred slurry of sodium hydride (389 of a 60~ dispersion in oil, 0.95M; prewashed with pentane) in dry tetrahydrofuran (200ml) at below 5C and under a gentle stream of dry nitrogen. The resulting mixture was stirred at room temperature for 1 hour and 4-methoxybenzyl chloride (123.2g, 0.79M) in dry tetrahydrofuran (100ml) was added. The resulting mixture was stirred at room temperature, protected from light, for 3 days.
The crude mixture was evaporated to dryness under reduced pressure, taken up in ethyl acetate (800ml) and filtered. The solvent was evaporated off under reduced pressure to afford a brown oil which was purified by column chromatography (silica gel, 5% hexane in t-butylmethyl ether to 5% methanol in t-butylmethyl ether to give l-12-[(4-methoxyphenyl)methoxy~-3-[(4-methoxy-phenyl)methoxylpropyl]-lH-imidazole as a colourless crystalline solid (1699), m.p. 73-74C (acetone-hexane).
Analysis found: C,68.84; H,6.88; N,7.21; C22H26N2O4 requires: C,69.09; H,6.85; N,7.32%. H-N~R(~-CDC13):

3.41(m,2H),3.55 (m,lH), 3.77, 3.79(2 singlets,6H)

4.06~m,2H), 4.43(m,4H) and 6.70-7.S0(m,11H).

1~74680 The following imidazole derivatives were prepared in the same manner as described for Example 1, by using the appropriately substituted benzyl alcohol/mercaptan (Ar CH2YH) and the appropriate benzylic compound ~ArCH2Z) Table 1 shows the structures of the aryl groups lArl and Ar), the heteroatom (Y) and the nucleofuge (Z) together with\ proton n.m.r. spectral data for the products. Where obtained melting points (m.p.) and analytical data for the compounds are also given.

~ . . P~ ~ m x u~ rq u~ u~ u~ ~
O O O 0~ ~ ~
~ 00 00 1~ t~ U~
r~7 ~ ~ ~ ~ r,~ ~ ~7 ~r _ ~ X _ X ~
~ ~, N ~ ~ _I `:C ~1 ~ ~ ~1 ~r ~ ~ ~ ~1 ~ ~ ~1 ~ _ ~1 _ _ ~1 ~ ~ ~ ~ ` P~ ~ ~ ~ ~ ~ ~ ~ ~
,~ ~n ~ ~ ~ ~ ~ ~ ~ ., ~ _ ,~ ~_ ~ ~ ~ ~_, ~ ~_ ~ _, -- O _ -- O _ -- O _ -- O _~ -- O
Il~ ~r In Il') ~ In Ir~ ~r In Il') ~r 11') Il~
U~ U~ u~ In ~r In ~ .
.. 1`
a O O O O O O
l~ ~ ~ ~ ~ ~
CO ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
N ~1 t~l ~1 ~ ~`I ~ ~ t~ ~
~;~ ~ ~ ~ ~ ~a ~ ~ ~ ~ ~ ~
Z_ _ "~ _ _ d _ -- ~d _ _ ,~ _ -- ~5 ,~ ~o ~ r~ ~ o u~ o ~r , o er o ~r ~ ~r ~ ~r d' ~ ~ ~ d' ~ ~r ~3 ~ 3 I _ __ ~, ~ ~ ~ ~
m :c m m p:
X X ~ ~U D U O

.
~ o o o o o \~

6~30 _ _..~ _ . _ .. , .. _ . _. __. _ . I. _ _ _ _ _ ~ ~` ~ _ ~`
:1~~ _. ~ X ~ X _T .,-.
(~I ~ ~J (~ ~1 r u, ~a u. u~ u~ ~n~n ~ u O ~ O 1- O ~ a~Il) r~) ~ _ ~~ r_ _ co ~ _I~ _Ir~ ~
_~ ~C. ~ :C ~ ~ ~r~) ~ 5 ~ X ~ ~r X
~O1`~0 O O ~ ~
au~~ ~~ :~ ~ ~~ ~~~ ~~~ ~ X ~ ~
U~ ~--3~ ~-- ,_ ~ _~ ~ _ ~ ~-- ~ ~--l` ~o ~ ~o ` ~o ~~ ~o ~ ~In ___ . ~_ . __ .__ .__, __ .
_ ~ t_ u~ o a~ l~~ ~ ~-- o u~ l_ In ~ IIl~ ~ I Il-) ~ I~ 1~ 1 U') ~ I ~ O I
~. .0 In 0 . .0 . Ø .0 0 Z~~ ~r 1~~ ~ 1- r~ ~~ ~r 1~
` `~D ~ `~D ` `~D ` `U~ ~ `~D
__ __ __ __ __X ~ a 1 C ~ ('`I
è ~~ ~ ~ ~ ~ ~ ~ ~~ u~
~D _ ~ U~ Or~l o ~r o~r ~~r ~ ~ ~~r .- ~
~er ~r r~er ~ ~r ~
' :~
~ ~ ~u ~l ~

~ ~. ~ ~ ~. ~ ~
m ~ T' 5: :~: ~ x ~ ~) ~) C~ ~) O ~
E~ O ' O O O O O
~ ~' .~ ~ ~ ~ ~

o O o . o O O

X O O O o o o .- - .
~ ~ ~ Jl ~

i I_ a) a~ .,o ,_ ~ .
~ L~- - l - - l ~-~74~80 _._ ,_ _ .__ ~ - .... __ ___ , ___ _ ~ ~ ~ ~ r r~ U~ ~1 N ~ r~
E U1 E~ u~ u) ~ Ul _ v~ E o u~--o U~r~l n~ ~D~ I~rl ` ~0 `
n ~r ~ ~ I~ ';r _ t~ ~r E ~ ~ 1~ 1` ~
~ 3~ . . _ . . _ ~ ~
~r ~ r~) ~r o ~ r o ~ o _ _ E _ _ E ---- E --~ r--

5: ::C ~ ~r ~ _ ~ ~ ~ i ~ ~r I ~ ~ ~
o ~ ~ o ~ ~ o ~ ~ o ~ ~ o ~ ~o O ~ E i_ E ~ E E ~ ~ E u~ . E ~
_ _ ~ _ _ I_ ~ ----~D ~ ----~D
O O O I O O ~ U~ OD I ~n o Lr) ~D In O
~o ~ ~ o ~r ~ o u~ o o u~ a ~ OD ~ ~ ~ ~:1 _ ~ ~ i~ ~ ` ~ ~ n~ .
~ ~ ~D
:~ ~ ~ ~ . _ ~ ~ _ _ ~ ~ _ _ _ _ _ ~ _ _ Z ~ ~ ~ ~ ~ ~ 3:: ~ X :~ ~ ~ ~
~,~. a a~ ~ ~r~ ~ ~ ~ ~ .
_ u) u) u~ E~_ ~ u~ u7 E u~ ~ E~
~ o o a~ o a~ o oo ~r ~ ~ a~ ~ a~ o oo rl t` ~r ~r . ~ _ _ ::~ ~ ~ ~ ~
iJ ! :C I C,) ~ !T!
~ ~ _ ~0 ~

_ ~rl ~ ~ ~ ~ ., :I: ~ :r ~ ~
E~ O O C~ i'~ O O

~1 O O O O O O

X O 'O O O O O
. .
_ -- _ ____ O U U_ U_ C~ U U
Z ~. ~r u~) ~D I~ C:) ___ __ .._..~ ___ _...._ .. _._ _ _. ___ ________ __ _ _ _ _ . _..__ ______ ___.__._ '_ ~7~680 _. .. _ ... _._ _ _. . a :r: .___ _ _ .
__ __ ~ O `~ __ _ u~ ~ u~ u~ o v~ u~ ~ . ul U) ~n o ~ o ~ ~ ~ ~ ~ ~ ~r a~ ~r o .~0 ~ ~ o~ ~ ~ a~ _ _-- . r~ o a~ .
. . ~: . ._ ~r: 3~ o 1- . .
~ ~ ~ ~r o r~ ~ ~ ~ ~ ~ In r~
_ _ _ _ ~ _ I~ _ ~ ~ ~ ~ .~ ~ .
~C I ~ u~ r ~ ___ . ~ ~1- ~ ~r~
a ~ c __--r- ----~D -- I I ~ __ ~__ ~
oo o ~ ~n ~In U~ n In ~ m ~-- u~ _ ~oU~ O ~ ~U~ ~ ~ ~ ~7 Ul ~ __ In ~ O ~ ~ O
_. . . _. . ~. . . ~ ~ . . U~ In C~~ ~ ~D O~ ~ ~ ~ ~ ~ ~ ~ ~
~~ ~ ~ .~ ~ ~~ ~n ~ ~ ~ I ~ ~ I
Z_ _ _ ~__ _ __ _ ~_~ _ _ _ _ O _ ~ O
I: ~ ~C II ~~ ~ .3:: ~ O ~
O ~ ~ ~~ ~ ~D ~ 1- U7 ~ ~ . ~ ~ .
. . ~ ~ ~D . ` ` ~D
~ ~ ~ Ul~ ~ ~ ~ ~ ~r ~ ~ ~ ~ ~ ~
_~U~ C~OO~ ~0 ~ CO `O ODO ~ ~0 ~r co er~ o a~~ _r~ _ ~ r~
. . .. . . . . 5: . . . .
r ~ ,~ ~ ~ _ ~r ~ ~r ~r , ~ ~ ~ .

r~ ,~ _ :r: :C ~: ~ 3: :1 ~ ~ ~J U ~I O
~ O O O O O O
-~: ~ ';~ ~ ~ ~ ~

o o o o o o X o o o o o o , __ _.__ - _l ~ ~ ~ ~ ~ u m C~ C~ ~
___ _ _ Z

E, ~ Q N ~ ~) ~r X _ N N N N N
~ .
__ .. ._ . ... _ .. ._ __ . _ ,,, __ _ 1,_ ,_ _ _ ,_,, _,_ _ __, , ,,~

1~74tj80 ~ .....

_ _ _ _ ... ~ . ._____, . ~-C 3-' 3-~ ___. _ 1~ C~ r~ ~) ~ ~ r~ ~
~ _ ~D U) ~ U~ ~ Ul ~ U)--_ U~
I :~: _ _ _ _ _ _-- :~:
r~ ~ oDa~ o~ o~ ~er~ ~
~ r~ ~D c~ ~o ~ ~cC~ ~ ` ~ _ ~ ~ ~ . . . . . .. . ~ ~r:
r~--~ r~r ~ ~ ~~ ~r U~ ~ U~ ~ .
o u~ ~ ~ . ~ ~ . ~ ~ .~ ~ ~r ~ ~ _ __ ._ ___ ___ __~~_ . _--~
~ r ~ r~ ~ ~ ~ C~ 1~ ~ Lr o ~N ~r ~ ~1 ~ ~ ~ _~ ~t ~~ ~ I .-- ~D .--~) ~ ~ .~ ~ ~~ ~ ~ ~ ~ ~ ~ ~o ~ .
_ ~r ~ E~ ~ ~
-- ~ ---- E~ ---- ~---- ~---- ~ -- I --In ~-- In n--u~ u~--u~ ~ ~D U~ O -~o ~ `_U~ ~ OU~ ~ O In ~ O U~ ~ ' In ~ ~r _~.U~ In .. ~ .~ .. ~ ...
~~~r r~ . ~ . ~ . ~ c r~r~
`1-'~ ~I ~I ~I ~ ~o z~ . _ ~ _ o_ _ o~ _ o_ _ ~_ _ 1~
:~ ~ ~ ~ ~ ~ 3~ ~~ ~ ~ ~ ~ -~ tn ~ ~J .~ r~ . N ~ ~1 ~I ~ (~ r`l ~D
_ ` `~D ~ `~
_ ~ ~ o o ~~I ~ C ~ ~ C a~ a~
~ . ~ ~ 1 ~1~ 0 t~ ~'1 0 ~ ~ ~ _ ~ ~r ~ er ~ ~~ e~ ~ ~
k~
a ~ ~ ~ C~

~1 ~ ~ ~ ~ ~ ~
~ ~ 5: ~ :~ U U
E~ O O O O O O
,~ ~ ..~ ~ ~ ~ ~' _ ~ o o o o o o :
X o o o o o o _ , _ :
~ a: ~ m Z ~ _ _ _ ~ U~ ~ I_ CO C~ ~ .
Cl .
. _ _ . __ _ . . . _ . . ._ _ _ _ __ _ _ _ _ _ . _ __ ~

~174680 --24~
_ :~ Z ,__ _ ,_ U~
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117~3V

- , :

Example 39 4-[[[1-(111-imidazol-1-yl)-2-~4-methoxyphenyl)methoxy]
ethoxy]methyl]benzoic acid 4-[[[1-(lH-imidazol-l-yl)-2-(4-methoxyphenyl) methoxy]ethoxy]methyl]benzoic acid, ethyl ester (Example 25, 12g) was treated with a 10% ethanolic solution of potassium hydroxide (30ml) and stirred at 18C for 24 hours. The solvent was evaporated of f under reduced pressure and the residue was treated with water (lOOml).
Acetic acid (5ml) was added to adjust the pH of the solution to pH S and the solution was extracted with dichloromethane. The combined extracts were dried (Na2S04) and the solvent was evaporated of f under reduced pressure to give the crude product which was-further purified by chromatography (silica'gel, 10% ethanol in dichloromethane) to give 4-[[Ll-(lH-imidazol-l-yl)-2-(4-methoxyphenyl)methoxy]ethoxy]methyl]benzoic acid.
Analysis found: C,65.53; 1I,h.16; N,6.79; C22H24N205-~H20 requires: C,65.17; H,6.21; N,6.91~
H-NMR(~-CDC13): 3.85-3.50~m,lH), 3.45(m,2H), 3.79(s,3H), 4.12(m,2H), 4.45(s,2H), 4.20-4.55(m,2H), 6.82-7.29(m,8H), 7.99-8.09(d,2H), and 10.73(s,1H).
l~xamples 40,41 The following derivatives in which the imidazoie ring is further substituted were prepared by the same procedure as used for Example 1, but using the appro-priately substituted imidazole. Table 2 shows the substitution pattern of the imidazole together with proton n.m.r. spectral date for the products.
R Table 2 N
O - CH2 ~ OCH3 O - CII2 ~ CH3 ,- , , '', ~ .
Example No. Rl R NMR ~S-CDC13) 2.30(s,3H), 3.45(m,2H), -CE13 H 3.60(m,~H), 3.75(s,3H), 3.78(s,3H), 3.95(m,2H), 4.30(m,2H), 4.43(s,2H), and 6.60-7.40(m,10H).

41 CH2CH3 -CH 1.25(t,3H), 2.15(s,3H), 3 2.60(q,4H), 3.45(m,2H), 3.50-4.00(2xs,m,8H), 4.06(m,lH), 4.25-4.60 (m,4H), 6.45(~lH), and

6.60-7.35(m,11ll).
. _ . ,, , ~, ' . .

1~7'}~

1-l3-1(4-Methoxyphenyl~methoxvl-2-13-(4-methoxyphenyl) 5 propyl-l-oxyl propylll -l}~-imidazole a) 3-(4-Methoxyphenyl)propan-l-ol, methane sulphonate Methyl sulphonyl chloride (12.59, 0.11M) was added dropwise to a stirred solution of p-methoxyphenylpropanol (16.6g, 0.10M) in dichloromethane (60ml)/pyridine (20ml) at 0C. The reaction mixture was maintained at 0C for 12 hours, then diluted with dichloromethane (250ml) and lS washed with hydrochlorid acid (5 x 50ml of SM.l 1). The solution was washed with water, dried (MgS04) and the solvent was evaporated off under reduced pressure to give 3-(4-methoxyphenyl)propan-1-ol, methane sulphonate (209), as a colourless crystalline solid, m.p. 41-42C
(pentane).

b) 1-13-~(4-l~ethoxyphenyl)methoxyl-2-l3-~4-methoxyphenyl) -propyl-l-oxy]propyl]-lH-imidazole.

1-12-Hydroxy-3-l(4-methoxyphenyl)methoxylpropyl-lH-imidazole (5.24g, 0.02M; prepared as in Example 1 (a)) was added to a stirred slurry of sodium hydride (0.889 of a 60% dispersion in oil, 0.022M) in dry dimethoxyethane (45ml) containing dry dimethylsulphoxide (2ml) under a 117~Q

gentle stream of dry nitrogen. The resulting mixture was stirred at room temperature for 0.5 hours and then treated with 3-(4-methoxyphenyl) propan-l-ol, methane sulphonate (5.37g, 0.022M) and stirred at 70C for a further 18 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in ethyl acetate (300ml), washed with water (4 x 50ml) and dried (MgS04). The solvent was ~ evaporated off under reduced pressure to give the crude product which was further purified by chromatography (silica gel, 10% pentane in chloroform) to give 1-[3-[(4-ltlethoxyphenyl)methoxyl -2-[3-(4-methoxyphenyl) propyl-1-oxy]propyl]-lH-imidazole (1.3g) as a colourless oil.
lH NMR (~-CDC13): 1.67-1.95 (m,2H), 2.55 (t,2~
3.10-3.65 (m,5H), 3.77 (s,3H), 3.80 (s,3H), 3.90-4.15 (m,2H), 4.43 (s,2H), and 6.60-7.50 (m,llH).

1-[3-~(4-Methoxyphenyl)methoxy]-2-[3(4-methoxyphenyl)-2-methylpropyl-l-oxy]propyl-lH-imidazole was prepared by the same procedure as for Example 42 but using 3-(4-methoxyphenyl~-2-methylpropanol, methane sulphonate.

1~7'~80 Example 44 1 [3-[3-(4-MethoxYphenyl)pro~yl-l-oxv]2-[(4-methoxY-nvl)methoxy]propyl]-lH-imidazole.
a) 2,3-Epoxypropyl-4-methoxyphenylpropyl ether 4-Methoxyphenylpropanol (15g, O.O90M) was added dropwise to a stirred slurry of sodium hydride (4.0g of a 60% dispersion in oil, O.lOM) in dry tetrahydrofuran (100 ml) and the stirred mixture was heated at 60C for 1 hour under a gentle stream of dry nitrogen. On cool-ing, épibromohydrin (12.8g, 0.0934M) was added and the mixture was stirred at ambient temperature for 65 hours.
The solvent was evaporated off under reduced pressure and the residue was treated with water (800ml) and extracted with dichloromethane. The combined extracts lS were dried (Na2S04) and the solvent was evaporated off under reduced pressure to give the crdue product which was further purified by chromotography (silica gel, dichloromethane) to give 2,3-epoxypropyl-4-methoxyphenyl-propyl ether as a colourless oil.
H-NMR(~-CDC13): 1.6-2.1(m,2H), 2.5-2.9(m,4H), 3.0-3.4(m, lH), 3.3-3.7(m,4H), 3.77(s,3H), 6.7-7.1(q,4H).
b) 1-[2-llydroxy-3-[3-(4-methoxyphenyl)propyl-1-oxy]
pro~yll-lll-imidazole 2,3-Epxoypropyl-4-methoxyphenylpropyl ether (12g, 0.054M) in dry acetonitrile (200ml) was treated with li74~80 imidazole (18g, 0.265M) and heated under reflux for 16 hours. The solvent was evaporated off under reduced pressure and the residue was treated with water (800~1) and extracted with dichloromethane. The combined extracts were dried (Na2S04) and the solvent was evapor-ated off under reduced pressure to give the crude product which was further purified by chromatography (silica gel, chloroform) to give 1-[2-hydroxy-3-~3-(4-methoxyphenyl)propyl-1-oxy]propyl]-lH-imidazole as a colourless oil.
c) l-[3-[3-(4-~ethoxYphenyl)propYl-l-oxY]-2-[(4-methoxyphenyl)methoxy]propyl]-lH-imidazole A solution of 1-[2-hydroxy-3-[3-(4-methoxyphenyl) propyl-l-oxy]propyl~-lH-imidazole (20g, 0.069M) in dry tetrahydrofuran (60ml) was added dropwise to a stirred slurry of sodium hydride (2.85 g of a 60~ dispersion in oil 0.0715M) and stirred at 0C for 15 minutes under a stream of dry nitrogen and then allowed to warm up to room temperature. The resulting mixture was stirred at room temperature for 1 hour and then heated under reflux for 1 hour under a stream of dry nitrogen. The solution was cooled to 15C and treated dropwise with 4-methoxy-benzyl chloride (llg, 0.071M) and stirred at ambient temperature for 65 hours in an inert atmosphere. The solvent was evaporated off under reduced pressure and 117~8~) ., the residue was treated with water (800ml) and extracted with dichloromethane. The combined extracts were dried (Na2S04) and the solvent was evaporated off under reduced pressure to give the crude product which was further purified by chromatography (silica gel, chloro-form) to give 1-13-[3-(4-methoxyphenyl)propyl-1-oxy]-2-~4-methoxyphenyl)methoxy)propyl]-lH-imidazole as a pale yellow oil.
lH-NMR(~-CDC13): 1.7-2.1(m,2H), 2.4-2.8(t,2H), 3.2-3.5 (m,6H), 3.78(s,6H), 3.9-4.2(m,2H), 4.3-4.4(d,2H), 6.70-

7.30(m,10H), and 7.45(s,lH).

117468~

EXAIlPLE 45 N-~(4-Methoxyphenyllmethyll-#-~I(4-methoxyphenvl)methoxyl methyll-lH-imidazole-l-ethanamine a) ~-[lt4-Methoxyphenvl)methoxylmethyll-lH-imidazole ethanol,4-methylbenzenesulphonate 4-Toluene sulphonyl chloride (18.0g, 0.094M) was added in portions to a stirred solution of 1-12-hydroxy-3-l~4-methoxyphenyljmethoxy]propyl]-lH-imidazole (31.4g, 0.12 M; prepared as in Example 1 (b)) in dry pyridine (100cm3)/dimethoxyethane (6~cm3) at 0C
over 0.5 hours. The solution was stirred at 0C for 4 hours. The reaction mixture was poured into ethyl acetate (1200ml), washed with water (4x200ml) and dried (MgS04). The solvent was evaporated off under reduced pressure to give the crude product as a yellow oil which was further purified by chromatography (silica gel, 10 ethanol in chloroform) to give ~-11(4-MethoxyPhenyl) methoxy)methyl]-lH-imidazole-l-ethanol,4-methylbenzene-sulphonate as a colourless crystalline solid (17g), m.p.
130-131C (ether-ethanol).

- ~17~680 -3~-b) 1-12-azido-3-~(4-Methoxyphenyl)nlethoxy]propyl]-IH-__ imidazole.

A solution ofd-llt4-Methoxyphenyl)methoxylmethyl]
-lH-imidazole-l-ethanol,4-methylbenzenesulphonate (6.3~g, 0.015M) dry dimethylformamide (30ml) was treated with sodium azide (1.699, 0.0225M) and heated at 70C for 16 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in ethyl acetate, washed with water and dried (MgS04). The solvent was evaporated off under reduced pressure to give the crude - product which was further purified by~chromatography (silica gel, 10% ethanol in chloroform) to give 1-12-azido-3-l(4-methoxyphenyl)methoxyl-2-azido]propyl]-1 Il- imidazole (3.6g) as a pale yellow oil.
lH-NMR (~-CDC13): 3.45 (m,2H), 3.60 (m,lH), 3.75 (s,3H), 4.00(m,2H), 4.45 (s,2H) and 6.70-7.45 (m,7H)~.

c) 1-12-amino-3-[(4-Methoxyphenyl)methoxylpropyl]-lH-imidazole.

A solution of 1-l2-azido-3-[~4-methoxyphenyl) methoxylpropyll-lH-imidazole (5.19, 0.018M) in dry tetrahydrofuran (10ml) was added dropwise to a stirred slurry of lithium aluminium hydride (0.68g, 0.018M) in dry tetrahydrofuran (40ml) at room temperature under a stream of dry nitrogen. When the addition was complete the reaction mixture was heated under reflux for 18 hours. The solvent was evaporated off under reduced pressure and the residue was extracted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and dried (MgS04). The solvent was evaporated off under reduced pressure to give 1-[2-amino-3-1(4-methoxyphenyl)methoxy]propyl]-lH-imidazole as an oil (3.69) which was used directly without further purification.
H-NMR (~-CDC13): 1.44(br.s,2H), 3.29(br.s,3H), 3.80(s,3H), 3.96(m,2H), 4.44(s,2H) and 6.60-7.45(m,7H).

d) N-1l4-Methoxyphenyllmethyll-~-ll(4-methoxyphenyl) ~ methoxvlmethvll-lH-imidazole-l-ethanamine.

A solution of 1-~2-amino-3-1(4-methoxyphenyl)methoxy~
propyll-lH-imidazole (1.709, 0.0065~1) in dry acetonitrile (10ml) containing triethylamine (0.5ml) was treated with 4-methoxybenzyl chloride (1.12g, 0.0072M) a~d heated under reflux for 18 hours under a stream of dry nitrogen.
The solvent was evaporated off under reduced pressure and the residue was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and dried (MgS04). The solvent was evaporated off under 1174~80 q reduced pressure to give the crude product as an oil which was further purified by chromatography (silica gel), 10%
ethanol in chloroform) to give N-[(4-methoxyphenyl)methyl]-~-[[(4-methoxyphenyl)methoxy]methyl]-1H-imidazole-1-ethanamine (0.09g) as a pale yellow oil.
H-NMR (~-CDC13) : 1.95 (broad s, 1H), 2.95(m,1H), 3.26(m,2H~, 3.68(s,2H), 3.78(s,3H), 3.79(s,3H), 3.98(d,2H), 4.40(s,2H) and 6.55-7.45(m,11H).
. EXAMPLE 46 1-[3-[(4-Methoxyphenyl)methoxy]-2-[[(4-methoxyphenyl)methyl]
thlo]propyl-lH-imidazole A solution of 4-methoxybenzyl mercaptan (1.65g, 0.0107M) in dry dimethoxyethane (5ml) was added dropwise to a stirred slurry of sodium hydride (0.52g of a 50% dispersion in oil, 0.0107M) in dry dimethoxyethane (20ml) containing dry dimethyl-sulphoxide (1ml). The resulting mixture was stirred for 0.5 hours and then treated dropwise with a solution of ~-[[(4-methoxyphenyl)methoxy]methyl]-1H-imidazole-1-ethanol, methylbenzenesulphonate (3.4g, 0.0089M) prepared as in Example 45 (a) in dry dimethoxyethane (5ml). The reaction mixture was stirred at room temperature for 2 hours and then at 60C for a further 18 hours. The solvent was evaporated off under reduced pressure and the residue was extracted with dichloromethane, washed with water and dried (MgS04). .

117468C) The solvent was evaporated off under reduced pressure to give the crude product as an oil which ~as further purified by chromatography (silica gel, 5~ ethanol in chloroform) to give 1-13-114-methoxyphenyl)methoxy~-2-5 ~[[4-methoxyphenyl) methyl]thiollpropyl~-lH-imidazole (0.069) as a pale yellow oil.
H NMR (S-CDCl3): 2.90 (quintet, lH), 3.36(m,3H), 3.53(s,2H), 3.77(s,3H) and 3.79(s,3H), 4.06(m,2H), 4.39(s,2H) and 6.60-7.45(m,llH).

The compound of Example l may be prepared as the two - optical isomers ~-and S- forms) which are described as Examples 47-48.

S-l-12-1(4-Methoxyphenvl~ methoxYl-3-1(4-methox~?henyl methoxvl~E?yll-lH-imidazole a) ~ Isopropylidene glycerol, 4-methylbenzene-sulphonate was prepared from S- ~ -isopropylidene glycerol and p-toluene sulphonyl chloride by the method of E. Baer and H.O.L. Fischer (J. Amer. Chem. Soç., 25 (1948), 70, 609) .

b) ~-l-(2,3-Dihydroxypropyl) -lH-imidazole A solution of R-~,~-isopropylidene glycerol, 4-methylbenzenesulphonate (4.59, 0.0l611) in acetonitrile ~174~80 .

(5ml) was treated with imidazole (3.219, 0.D47M) and heated under reflux for 18 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in dichloromethane (150cm3), washed with water 5 and dried (MgS04) . The resulting crude protected imidazole propane-diol was then treated with hydrochloric acid (3ml of 5 Molar) and heated at 60C for 1.5 hours.
The excess hydrochloric acid was evaporated off under reduced pressure to give 10 ~ (2,3-dihydroxypropyl)-lH-imidazole,hydrochloride as a hygroscopic soiid.
H-NMR (~-(CD3) 2S0): 3 0~4 5 ( m,7H) ~ r7.6~7.8(m~2H)~ 9-1 s,lH) 15 c) A solution of ~-1-(2,3-dihydroxypropyl)-lH-imidazole, hydrochloride (0.829, 0.005M) in dry dimethylsulphoxide (2ml) was added to a stirred slurry of sodium hydride (~.7~9 of a 50% dispersion in oil, 0.0165M) in dimethoxyethane (15ml) at 0C under a stream of dry 20 nitrogen. The reaction mixture was stirred at 18C for 2 hours and then treated with a solution of 4-methoxybenzyl chloride (1.729, 0.011M) in dry dimethylsulphoxide (2ml~
and stirred for a further 18 hours. The solvent was evaporated off under reduced pressure and the residue was 25 treated ~ith water and extracted with ether. The combined ether extracts were washed with water, dried (llgS04), and 117~80 the solvent was evaporated off under reduced pressure to give the crude product which was further purified by chromatography (silica gel, 10% ethanol in chloroform) to give ~-1-12-~(4-methoxyphenyl)methoxy]-3-[(4-methoxyphenyl) methoxy]propyl~-lH-imidazole, 1~]527q - 26.98.

_ 3-1~4-Methoxyphenyl)methoxyl-2-1~4-methoxyphenyl) methoxy]propyl)-lH-imidazole a) ~-l-benzyloxy-2,3-dihydroxypropane S-~,~-Isopropylidene glycerol (2.53g, 0.0191M) was added dropwise to a stirred slurry of sodium hydride (1.08g of a 50% dispersion in oil, 0.021M~ in dry dimethoxyethane (15ml) containing dry dimethylsulphoxide (3ml). The reaction mixture was stirred at room temperature for 0.25 hours and then treated ~ith benzyl chloride (2.669, 0.021M). The reaction mixture was heated at 80 C for 3 hours. The solvent was evaporated off under reduced pressure and the residue was treated with water and extracted with ether. The combined extracts were dried (r~lgs04) and the solvent was evaporated off under reduced pressure to give the crude ~ -isopropylidene glycerol, benzyl ether. The crude

8~

product was dissolved in acetone (4ml) and treated with hydrochloric acid (2ml of lMl 1) and heated at 70C for 2 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in ethyl acetate (120ml), washed with saturated aqueous sodium hydrogen carbonate solution and dried (~JgS04). The solvent was evaporated off under reduced pressure to give the crude product which was further purified by chromatography (silica gel, 10% ethanol in chloroform) to give B-l-benzyloxy-2,3-dihydroxypropane ~3.29) as an oil.

_ b) ~-[(l-benzyloxy-2,3-dihydroxypropane) r3~ ( 4-methylphen-yl)sulphonate p-Toluene sulphonyl chloride (6.86g, 0.036M) was added in portions to a stirred solution of B-l-benzyloxy-2,3-dihydroxypropane (6.0g, 0.033M) and dry pyridine (7ml) in dry dimethoxyethane (22ml) at -40C.
The reaction mixture was then kept at 0C for 18 hours.
The solvent was evaporated off under reduced pressure and the residue was dissolved in ether (200ml), washed with hydrochloric acid (3x20ml of lMl 1), washed with saturated aqueous sodium hydrogen carbonate solution (2x20ml) and dried (MgS04). The solvent was evaporated off under reduced pressure to give the crude product which was further purified by chromatography (silica gel - 2% ethanol in chloroform) to give ~-[(l-benzyloxy-2,3-dihydroxypropane),3-(4-methylphenyl) sulphonate (l.lg) as an oil.

117~

c) B-~ -(3-Benzyloxyl-2-hydro~:y)propy~ -imidazole A solution of ~ -benzyloxy-2~3-dihydroxypropane)~
3-(4-methylphenyl)sulphonate (2.5g, 0.0072M) in dry acetonitrile (7ml) was treated with imidazole (1.479, 0.0217M) and heated under reflux for 18 hours. The solvent was evaporated off under reduced pressure and the residue was treated with water and extracted with ethyl acetate. The combined extracts were dried ~MgS04) and the solvent~ was evaporated off under reduced pressure to give the crude product which was further purified by - chromatography (silica gel, 15% ethanol in chloroform) to give B-~ -(3~benzyloxy-2-hydroxy) propyl]-lH-imidazole ( 1 . l9g) .
d) B-l-[l-(2~3-Dihydroxy) propyl]-113-imidazole, hydrochloride A mixture of B-1-(3-benzYloxy-2-hYdroxYpropyl)-lH-imidazole (1.09, 0.0043M) and 1096 palladium on charcoal (0.39) in ethanol (12ml) containing 5 drops of ethereal hydrogen chloride was stirred under an atmosphere of hydrogen for 24 hours. The solution was filtered and the solvent was evaporated off under reduced pressure. The residue was dissolved in ethanol and acidified with ethereal hydrogen chloride to give B-1-11-(2;3-dihydroxy) propyl]-1~3-imidazole, hydrochloride.

1~7~

.

e) R-1-[2-[(4-methoxyphenyl)methoxy]-3-[14-methoxyphenyl) methoxy]propyl]-lH-imidazole R-1-[1-~2,3-Dihydroxy)propyl]-lH-imidazole, hydrochloride was reacted with 4-methoxybenzyl chloride using the procedure described in Example 47 (c) to give R-1-[2-[(4-methoxyphenyl)methoxy]-3-[(4-methoxyphenyl) methoxy]propyl ? - lH-imidazole, [a~589 + 22.08.

117~680 BIOLOGICAL EVALUATION

The compounds of the invention have been tested by the following in vitro radioimmunoassays for their ability to inhibit thromboxane and affect prostacyclin production.

In vitro tests Thromboxane production in Human Platelet Rich Plasma a) Platelet rich plasma (prp) preparation Human venous blood was collected from healthy male donors, who had denied any medication during the previous 14 days. Nine volumes of blood were mixed with one volume of 3.24~ trisodium citrate. The citrated blood was centrifuged at 160 g for 10 mins. at 22C to obtain platelet rich plasma (prp). The platelets were then counted on a Coulter counter, and the platelet count was adjusted to 200,000 per ~1 with plasma.

b) Thromboxane generation The prp was then dispensed as aliquots into micro-Eppendorf tubes, maintained at 37C in a dry bath. The compounds, dissolved either in saline, ethanol, or dimethylsulphoxide, were added in duplicate to the prp aliquots to produce final concentrations in the range of 0.1-30 ~g/ml. When ethanol and DMSO were used as the vehicle, triplicate controls containing the same percentage of vehicle as the test compounds were made.

-'/3-.

117~0 -44~
The final concentration of organic solvent was never more than 0.1%, which in previous experiments had no effect on Txs2 generation.
Following a 10 min. incubation with test compounds or vehicle, collagen was added to produce a final concentration of 20 ~g/ml. The tubes were then whirly-mixed for 15 seconds and replace~ in the dry bath for a further 10 minutes, controls received saline instead of collagen. The reaction was then stopped by rapid centrifugation (15000 g for 3 mins). The plasma was removed and frozen at -29C until assayed.

c) Assay of Thromboxane B2 Briefly, 100 ~1 aliquots of the following, in 50 mM
phosphate buffer + 0.1% gelatin + Thimerosal (pH 6.8) were incubated together for 16 hour~ at 4C: thromboxane TxB2 (plasma extract or standards 50 to 10,000 pg/ml), [3H] - TxB2 (approximately 15,000 dpm) and anti-Txs2 antiserum (0.5 ~g/100 ~1). The free and protein bound [3H] - TxB2 were separated by adsorption onto activated charcoal followed by centrifugation. 1.0 ml of the supernatant was added to an aqueous scintillation fluid, and the radioactivity present was counted in a liquid scintillation counter. The binding of [ H] - TxB2 in the absence of added TxB2 was approximately 55%. The least amount of Txs2 to be detected accurately in the plasma was 50 pg/ml. Cross reactivity with other prostaglandins is less than .005% except PGD2 which is 1%.

~k 1~.7~

Thus plasma samples were assayed to give a rough approximation of Txs2 content. The plasma was then appropriately diluted and assayed in duplicate to give accurate values.

d) Analysis of Results The amount of TxB2 generated by the collagen was calculated by subtracting mean values obtained for the saline stimulated platelets from the mean values obtained from the collagen stimulated platelets. Then the amount of TxB2 generated in the presence of each concentration of compound was expressed as a % control and dose response curves were then constructed to determine the -concentration of compound which produced a 50%
inhibition. These values known as the IC50 obtained for various compounds tested are given in Table 3 below.

1~7~ 0 COMPOUND ACTIVITY
(13XAMPLE NO) (IC50x10 M) Prostae clin Produetion in Cultured Aortic Endothelial Cells Y

a) Cell culture Bovine aortic areh tissue was obtained from a local abattoir, and transported to the laboratory on ice.
Arterial endothelial cells were obtained from the washed (phosphate buffered saline) aortic arch tissue by gentle scraping of the intima, within two hours of sacrifice.
Cell suspensions were washed by centrifugation, resuspended, and propagated in Roswell Park Memorial Institute (RPMI) 1640 medium ~Moore, G.E., J.A.M.A., (1967), 199, 519) 1640 medium + 20% foetal calf serum (FCS) + antibiotics (1-2 doublings). The cells were then trypsinised, cloned by limiting dilution, selected colonies grown to confluence (3-4 passages), and stored in liquid nitrogen. When required, batches of cells were removed from store, resuscitated, and propagated in RPMI
medium + 10% FCS + antibiotics (passaged 6-15 times). At 11~7~

trypsinisation, representative cells from each passage were transferred to multiwell plates (1 x 105 cells/well) and incubated for 3 days (final count 3.5 x 105 cells/well).
The medium in each well of the plate was exchanged for serum and antibiotic free RPMI 1640, and a time 0 sample (100 ~1) taken. Drugs or vehicle were next added as required, and a further sample (800 ~1) taken from each well after a 60 minute incubation at 37C with gentle shaking. Prostacyclin synthesis and release into the medium over this period was estimated using an RIA
technique for 6-keto PGFl~ , the stable metabolite of PGI2 (New England Nuclear 6-keto PGFl~ RIA kit, Catalogue No.
NEX 008).

b) Assay of 6-keto PGFl~
Briefly, 100 ~1 aliquots in 50 mM phosphate buffer +
0.1~ gelatin + 0.01~ thimerosal (pH 6.8) of the following were incubated together for 16 hours at 4C: 6-keto PGFla (incubation medium extract or standards 10-1000 pg/O.lml), [ H~-6-keto PGFl~ (approximately 15000 dpm) anti-6-keto PGFl~ antiserum. The free base and protein bound [3H]-6-keto PGFl~ were separated by adsorption onto activated charcoal followed by centrifugation. 850 ~1 of the supernatant was added to an aqueous scintillation fluid, and the radioactivity present counted in a liquid scintillation counter. The binding of [3H]-6-keto PGFl~ in the absence of added 6-keto PGFl~ was approximately 40%.
The least amount of 6- keto PGFl~ to be detected accurately in the samples was 100 pg/ml. Cross reactivity with other prostaglandins was less than 0.3%
except PGE2 (2%) and PGF2~ (2.7%).

.~

1~i7~6~3~

By means of exemplification the data obtained for the compound of Example 1 is given below in Table 4.

Effect of Example I on PGI synthesis in cultured bovine arterial endothelial cells in vitro Example I Net PGI2 synthesis (~m) (pg 6-keto PGFl~/60min/3.5xlO5cells) Change o 120 2.6 125 +4 7.8 130 +8 26.0 106 -12 78.0 135 +12 CONCLUSION

Table 4 shows that at in vitro concentrations substantially in excess of those which inhibit platelet thromboxane synthetase, Example 1 has no significant effect on basal PGI2 synthesis in cultured bovine aortic endothelial cells over an incubation period of 1 hour.

6~

Inhibition of Platelet Aggregation in vitro In addition to the above tests, platelet aggregation in citrated prp (prepared as above) against a variety of aggregating agents was measured turbidometrically in a Payton Dual Channel Aggregometer (method as described in G.V.R. Born, Nature, (1962), 194, 927).
Compounds of the invention tested in this way actively inhibited both collagen and arachidonic acid induced aggregation of human prp in a dose related fashion. Thus, for purposes of exemplification, in this respect compounds of Example 1 and Example 20 were clearly more active than aspirin, dipyridamole, or sulphinpyrazone (Table 5).

I-C 50 (~M) vs COLLAGEN ARACHIDONIC ACID

DIPYRIDAMOLE >200 >200 117~680 1L-~VO mod~l ' The retired breeder male rat may be utilized any time from 24 hours to 6 months after receipt without prior fasting or manipulation. The assay has been demonstrated to give consistent results without regard to the time of day or season of the year. The test (as described in R.~. Saunders, T.S. Burns, ll.R. Selzer and ~.R. ~askawic, Lab.Animal Sci., (1977), 27~ 757-761) consists of the oral administration of the investigative compound either dissolved in or suspended in propylene glycol 40~ at 2 - mg/kg to four retired breeder male rats (4~ mg of compound required). Three hours from the time of administration, the rats are ether anaesthetized, the abdominal cavity exposed and one ml of blood is withdrawn into each of two syringes from the vena cava. The first syringe contains four ml of buffered citrate~formalin solution and the second syringe contains four ml of buffered citrate alone. The syringes are inverted, held at room temperature for 15 minutes and the contents are centrifuged at 170 9 for 14 minutes. Platelet counts are obtained on the undiluted solutions by means of a hemacytometer under 430 X phase-contrast microscopy. The platelet aggregate ratio is obtained by dividing the platelet count of the first syringe by that of the second syringe. A ratio of 1.~ would indicate that no platelet o aggregates are present whereas ratios below 1.0 indicate the presence and degree of platelet aggregate formation which has occurred. If an aggregate ratio of 0.85 or great:er is observed, the compound is considered active at the P< 0.05 level ~see statistical analysis attached).
The untreated retired breeder rat has an aggregate ratio of 0.76 + ~.02 whereas a virgin rat of the same age, sex, strain and supplier has a ratio of 0.94 + ~.02. A
compound found active at the screening dose may be further evaluated at lower doses to produce an ED50 or the dose at which the aggregate ratio is half way returned to the virgin rat value.

r, G
.

COtlP~RlSOI~l OF ~NTIPLATELET ACTIVITY OF EXAIIPLE 1 AI~D Ey~A~lPLE 2 ~ITH TH~T OP OTHER ANTI-~GGREG~TORY AGENTS IN THE
~ALE BREEDER RAT

Compound x50 (3h post oral ~ administration) EXAIIPLE 1 0.49 mg/kg EXAMPLE 20 1.8 r,lg/kg aspirin 7.7 mg/kg dipyridamole 6.8 . mg/kg (Persantine) sulflnpyrazone 4.1 mg/kg (Anturane)

Claims (38)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. A process for the preparation of a compound of the formula I:

I
or an acid addition salt thereof;
in which Ar and Ar1, which may be the same or different, each represents an aromatic radical which may be substituted by one or more substituents selected from the following halogen; carboxy;
lower alkyl; carboxyalkyl;
lower alkoxy; cyano;
alkylenedioxy; carboxamido;
aralkoxy; di-lower alkylamino;
aryloxy; nitro; and trihalomethyl; lower alkyl sulphonyl provided that one of the groups Ar and Ar1 carries at least one alkoxy, alkylenedioxy, carboxy or carboxy alkyl substi-tuent; and Alk1 and Alk2, which may be the same or different, each represents an alkylene group containing from 1 to 8 carbon atoms which may be substituted one or more times by lower alkyl;
X and Y, which may be the same or different, each re-presents oxygen, nitrogen or sulphur;
and in which the imidazole ring may be substituted by one or more lower alkyl substituents, which comprises either (a) reacting a compound of the formula II:

II

in which Y, Alk1 and Ar1 have the meanings given above and in which the imidazole ring may be substituted with one or more lower alkyl substituents, with a compound of the formula III:
III Q1Alk2Ar in which Q represents a group of the formula XH in which X
has the meaning given above and Q1 represents a nucleophilic-displaceable group or vice versa and Alk2 and Ar have the meanings given above; or (b) for the production of a compound of formula I in which X, Y, Alk1, Alk2, Ar and Ar1 have the meanings given above with the proviso that X-Alk2-Ar is identical to Y-Alk1-Ar1, reacting a compound of the formula IIa:

IIa in which Q has the meaning given in (a) above, with an appro-priate amount of a compound of the formula III:
III Q1Alk2Ar in which Q1 has the meaning given above; or (c) subjecting a compound of formula I containing one or more carboxyalkyl substituents to basic hydrolysis to pro-duce a compound of formula I containing one or more carboxy substituents; or (d) converting a compound of formula I to an acid addi-tion salt thereof.

2. The proeess as claimed in claim 1 for the prepara-tion of a compound in which X is oxygen wherein the compound in which Q represents the group XH in which X is oxygen is reacted with a compound of the formula Q1Alk2Ar in which Q1 represents a nucleophilic-displaceable group.

3. The process as claimed in claim 1 for the prepara-tion of a compound in which X represents NH wherein a compound in which Q represents the group NH2 is reacted with a compound of the formula Q1Alk2Ar in which Q1 represents a nucleophilic-displaceable group.

4. The process as claimed in claim 1 for the prepara-tion of a compound in which X represents S wherein a compound in which Q represents a nucleophilic-displaceable group is reacted with a compound of the formula Q1Alk2Ar in which Q1 represents a group HS-.

5. The process as claimed in claim 1(b) for the pre-paration of an individual optical isomer wherein the imidazole starting material of the formula has a known optical integrity.

6. The process as claimed in claim 1 in which each alkoxy group contains from 1 to 6 carbon atoms.

7. The process as claimed in claim 1 in which each alkoxy group contains from 1 to 4 carbon atoms.

8. The process as claimed in claim 1 in which the alkoxy groups are selected from methoxy and ethoxy.

9. The process as claimed in claim 1 in which the alkylenedioxy group contains 1 to 3 carbon atoms in the alky-lene chain.

10. The process as claimed in claim 1 in which the alkylenedioxy group is methylenedioxy.

11. The process as claimed in claim 1 in which the carboxyalkyl substituent is carboxymethyl or carboxyethyl.

12. The process as claimed in claim 1 in which, when an aryloxy substituent is present, the substituent is phenoxy.

13. The process as claimed in claim 1 in which, when an aralkoxy substituent is present, the substituent is ben-zyloxy.

14. The process as claimed in claim 1 in which Ar and Ar1 each represent a moiety selected from phenyl, naphthyl, pyridyl, furanyl and thienyl, which may be substituted as specified in claim 1.

15. The process as claimed in claim 1 in which Ar and/or Ar1 represent phenyl, furanyl, thienyl or pyridyl optionally substituted by one or more of the following sub-stituents, namely, lower alkoxy, methylene dioxy, carboxy and carboxy lower alkyl.

16. The process as claimed in claim 1 wherein the compound thus prepared is 1-[2-[(4-methoxyphenyl)methoxy]-3-[(4-methoxyphenol)methoxypropyl]-1H-imidazole.

17. The process as claimed in claim 1 wherein the compound thus prepared is 1-[2-[(4-methoxyphenyl)methoxy]-3-[3,4-methylenedioxyphenyl)methoxypropyl]-1H-imidazole.

18. The process as claimed in claim 1 wherein the compound thus prepared is 4-[[[1-(1H-imidazol-1-yl)-2-(4-methoxyphenyl)methoxy]ethoxy]methyl]benzoic acid ethyl ester.

19. The process as claimed in claim 1 wherein the compound thus prepared is 4-[[[1-(lH-imidazol-1-yl)-2-(4-methoxyphenyl)methoxy]ethoxy]methyl]benzoic acid.

20. A compound of the formula I:

or an acid addition salt thereof;
in which Ar and Ar1, which may be the same or different, each represents an aromatic radical which may be substituted by one or more substituents selected from the following halogen; carboxy;
lower alkyl; carboxyalkyl;

lower alkoxy; cyano;
alkylenedioxy; carboxamido;
aralkoxy; di-lower alkylamino;
aryloxy; nitro; and trihalomethyl; lower alkyl sulphonyl provided that one of the groups Ar and Arl carries at least one alkoxy, alkylenedioxy, carboxy or carboxy alkyl substi-tuent; and Alk1 and Alk2, which may be the same or different, each represents an alkylene group containing from 1 to 8 carbon atoms which may be substituted one or more times by lower alkyl;
X and Y, which may be the same or different, each re-presents oxygen, nitrogen or sulphur;
and in which the imidazole ring may be substituted by one or more lower alkyl substituents, when prepared by the process of claim 1.

21. A compound as defined in claim 20 wherein X is oxygen, when prepared by the process of claim 2.

22. A compound as defined in claim 20 wherein X re-presents NH, when prepared by the process of claim 3.

23. A compound as defined in claim 20 wherein X re-presents S, when prepared by the process of claim 4.

24. A compound as defined in claim 20 in the form of an individual optical isomer, when prepared by the process of claim 5.

25. A compound as defined in claim 20 in which each alkoxy group contains from 1 to 6 carbon atoms, when prepared by the process of claim 6.

26. A compound as defined in claim 20 in which each alkoxy group contains from 1 to 4 carbon atoms, when prepared by the process of claim 7.

27. A compound as defined in claim 20 in which the alkoxy groups are selected from methoxy and ethoxy, when pre-pared by the process of claim 8.

28. A compound as defined in claim 20 in which the alkylenedioxy group contains 1 to 3 carbon atoms in the alky-lene chain, when prepared by the process of claim 9.

29. A compound as defined in claim 20 in which the alkylenedioxy group is methylenedioxy, when prepared by the process of claim 10.

30. A compound as defined in claim 20 in which the carboxyalkyl substituent is carboxymethyl or carboxyethyl, when prepared by the process of claim 11.

31. A compound as defined in claim 20 in which, when an aryloxy substituent is present, the substituent is phenoxy, when prepared by the process of claim 12.

32. A compound as defined in claim 20 in which, when an aralkoxy substituent is present, the substituent is benz-yloxy, when prepared by the process of claim 13.

33. A compound as defined in claim 20 in which Ar and Ar1 each represent a moiety selected from phenyl, naphthyl, pyridyl, furanyl and thienyl, which may be substituted as specified in claim 20, when prepared by the process of claim 14.

34. A compound as defined in claim 1 in which Ar and/or Ar1 represent phenyl, furanyl, thienyl or pyridyl op-tionally substituted by one or more of the following substi-tuents, namely, lower alkoxy, methylene dioxy, carboxy and carboxy lower alkyl, when prepared by the process of claim 15.

35. The compound of claim 20 which is 1-[2-[(4-methoxyphenyl)methoxy]-3-[(4-methoxyphenol)methoxypropyl]-1H-imidazole, when prepared by the process of claim 16.

36. The compound of claim 20 which is 1-[2-[(4-methoxyphenyl)methoxy]-3-[3,4-methylenedioxyphenyl)methoxy-propyl]-1H-imidazole, when prepared by the process of claim 17.

37. The compound of claim 20 which is 4-[[[1-(1H-imidazol-1-yl)-2-(4-methoxyphenyl)methoxy]ethoxy]methyl]-benzoic acid ethyl ester, when prepared by the process of claim 18.

38. The compound of claim 20 which is 4-[[[1-(1H-imidazol-1-yl)-2-(4-methoxyphenyl)methoxy]ethoxy]methyl]-benzoic acid, when prepared by the process of claim 19.